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Crystal structure of aurora-2, an oncogenic serine/threonine kinase
Graham M T Cheetham1, Ronald M A Knegtel, Joyce T Coll
1Vertex Pharmaceuticals (Europe) Ltd., 88 Milton Park, Abingdon, Oxfordshire OX14 4RY, United Kingdom. cheetham@vpharm.com
Abstract:
Aurora-2 is a key member of a closely related subgroup of serine/threonine kinases that plays important roles in the completion of essential mitotic events. Aurora-2 is oncogenic and amplified in various human cancers and could be an important therapeutic target for inhibitory molecules that would disrupt the cell cycle and block proliferation. We report the first crystal structure of Aurora-2 kinase in complex with adenosine. Analysis of residues in the active site suggests differences with structurally and biologically related protein kinases. The activation loop, which contains residues specific to the Aurora family of kinases, has a unique conformation. These results provide valuable insight into the design of selective and highly potent ATP-competitive inhibitors of the Aurora kinases.
Insights
Aurora-2 kinase, a target for cancer therapy, has its crystal structure revealed. This finding aids in designing potent inhibitors to block cancer cell proliferation.
Area of Science:
- Molecular Biology
- Structural Biology
- Oncology
Background:
- Aurora-2 is a serine/threonine kinase crucial for mitosis.
- It is oncogenic and amplified in human cancers, making it a therapeutic target.
- Inhibiting Aurora-2 can disrupt the cell cycle and block cancer proliferation.
Purpose of the Study:
- To determine the first crystal structure of Aurora-2 kinase.
- To analyze the active site and activation loop for drug design insights.
- To provide a basis for developing selective ATP-competitive inhibitors.
Main Methods:
- X-ray crystallography was used to obtain the Aurora-2 kinase structure.
- The structure was determined in complex with adenosine.
- Analysis focused on active site residues and the activation loop conformation.
Main Results:
- The first crystal structure of Aurora-2 kinase bound to adenosine is reported.
- Active site analysis revealed differences compared to related kinases.
- A unique conformation of the Aurora kinase-specific activation loop was observed.
Conclusions:
- The determined structure provides valuable insights into Aurora-2 kinase.
- Understanding the active site and activation loop is key for inhibitor design.
- These findings facilitate the development of selective and potent ATP-competitive inhibitors for Aurora kinases.